Natural killer cells (NK) are a component of the innate immune system and are specialized to kill virally infected host cells. An early, strong immune response to HIV is an advantage in controlling the virus, and studies have shown that patients with more rapid disease progression have decreased NK activity. The highly polymorphic, NK surface receptors, known as the Killer Immunoglobulin-like Receptors (KIR), act to regulate NK activation. Our preliminary data support the hypothesis that specific inhibitory and activating NK receptors may play an important role in HIV transmission and disease progression. We propose to examine the role of KIR genotypes and KIR with their HLA ligand associations in the in the Chicago MACS population. We have the unique advantage of examining this cohort, as our team has already analyzed the HLA allelic and supertype associations with disease in this population. To perform this work, we propose to develop an innovative and novel, high-throughput, single nucleotide polymorphism (SNP)-based method for genotyping the KIR loci using matrix-assisted laser desorption/ionization time-of flight (MALDI-TOF) mass spectrometry. The novel SNP-based method is superior to alternative genotyping methods, with an accuracy rate of >99% with duplicates, and with unparalleled efficiency of sample utilizing only 2 ng of DMA per multiplex reaction. By developing this unique and high-throughput KIR genotyping method using the MALDI, we will be able to accurately genotype the KIR complex in 1,000 MACS samples, including roughly equal numbers of high risk negative control and HIV-positive samples. As the first population-based study of the role of KIR heterogeneity and KIR-HLA associations with HIV disease, and the first study to address the role of KIR in HIV transmission, this analysis promises to significantly further our understanding of host genetic factors in HIV disease control. Data from this study will be critical to future studies examining the functional significance of KIR gene expression in HIV disease. [unreadable] [unreadable]